The goal of this Program Project is to develop novel vaccination strategies for oral carcinoma. It consists of four research projects, three cores and three clinical trials, with a plan to introduce peptide derived from human oral carcinomas and modified dendrite cells (DC) as vaccines in additional trials in subsequent years. Cancer of the oral cavity has one of the lowest five-year survival rates among all cancers. Improvements in survival of patients with oral carcinoma are most likely to come from the development of novel approaches to therapy and more effective strategies to prevent the development of primaries in individuals at high risk of oral squamous cell carcinoma (OSCC) and to eliminate recurrence or development of second primary cancers in patients with OSCC initially treated with conventional therapy. To meet the existing need for novel therapies in OSCC, the proposed Program will foster translational research aimed at advancing basic findings in the biology of OSCC to clinical trials. To meet these objectives, the Program Project is designed to bring together basic and clinical investigators with an interest in oral cancer in order to develop and evaluate effectiveness of vaccines that are expected to prevent primary oral cancer, its recurrence or appearance of second primary tumors. Research efforts will include identification and characterization of new immunologic peptides derived from OSCC, evaluation of synthetic p53- derived peptides and autologous DC for the ability to induce cytotolytic T lymphocyte (CTL responses), and examination of the role of the cytokine, IL-12, in modulation of anti-OSCC responses. Immunosuppression, which is common is patients with OSCC, will be studied at the level of signalling molecules, and possibilities for its reversal will be explored. Therapeutic goals include preclinical and clinical evaluations of vaccines with OSCC-derived peptides and HLA-matched DC, wild type p53 gene replacement theory, and studies with the cytokine, IL-12, to promote TH1 antitumor response. Complementary clinical trials with systemic IL-12 or with IL-12 gene therapy will be performed. Administrative, tissue procurement/DC laboratory and clinical support/biostatistics cores will support this basic and clinical vaccination program. The proposed novel immunologic approaches to therapy of OSCC are based on recent progress in DC biology, improved knowledge about antigen processing and delineation of defects in immune reactivity. This Program Project has a long-term objective of improving survival of OSCC patients through vaccination strategies.